Many regulatory proteins are themselves tightly controlled by ubiquitin conjugating and deconjugating enzymes, whose dysfunctional forms are implicated in numerous diseases, including cancers. USP7, a deubiquitylating enzyme, regulates ubiquitylation and, thereby, stability of the E3 ligase HDM2, which in cells effects ubiquitylation and promotes proteasomal degradation of the tumor suppressor p53 as well as a number of other proteins such as FOXO4, PTEN and claspin. Thus, inhibiting USP7 can impact both p53 wild type and mutant tumors. In addition, by de-ubiquitylating and preserving the transcription factor Foxp3, USP7 increases T regulatory cell (Treg) mediated suppression of tumor-infiltrating T effector cells, the latter being associated with improved clinical outcome for many solid tumors, including lung cancers. Thus, USP7 functions to limit immune cell-mediated antitumor defenses. The observation that the accumulation of Foxp3+ Treg cells at the tumor or in draining lymph nodes signals poor prognosis further highlights the significance of this recently described second oncogenic mechanism of USP7. Thus, inhibitors of USP7 can exert in vivo antitumor activity by: 1) directly inhibiting tumor cell proliferation via Hdm2 and other targets; and 2) suppressing T regulatory cells via Foxp3, thereby facilitates the antitumor function of T effector cells. Progenra has discovered and initiated chemical exploration of the selective USP7 inhibitor P0005091 (IC50= 4.2M), which demonstrates p53-independent antitumor efficacy in several multiple myeloma and leukemia models and down-regulates Foxp3, preventing Treg mediated immune suppression without impairing T effector function in vivo. Moreover, P0005091 is active against syngeneic AE17 mesothelioma in immunocompetent but not SCID/nu animals, demonstrating that in this model efficacy is due to T cell energy, not cytotoxicity. It is now proposed to continue chemistry on the P0005091 series to improve the potency and drug-like properties of the compounds using standard medicinal chemistry approaches. New analogs will be evaluated biochemically and the most promising compounds will also be studied in cellular and in vivo models of T cell activity to achieve lead optimization and in vivo proof of concept, resulting in the identification of candidate compound(s) for preclinical development in Phase II.